Sequential Chemoradiotherapy Combined with Immunotherapy Versus Sequential Chemoradiotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: A Multicenter Retrospective Cohort Study with Propensity Score Matching

Sequential Chemoradiotherapy Combined with Immunotherapy Versus Sequential Chemoradiotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: A Multicenter Retrospective Cohort Study with Propensity Score Matching | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Sequential Chemoradiotherapy Combined with Immunotherapy Versus Sequential Chemoradiotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: A Multicenter Retrospective Cohort Study with Propensity Score Matching Qinghua Xu, Xiaoshuai Yuan, Shuyan Meng, Guanghui Gao, Chenglong Sun, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8849122/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract We aimed to assess the real-world effectiveness and toxicity of immune checkpoint inhibitor (ICI) treatment in unresectable stage III non-small cell lung cancer (NSCLC) patients who received ICIs before and after sequential chemoradiotherapy (sCRT) versus those who received sCRT alone.The study's primary endpoint was to evaluate the survival benefits of the treatment approach, with a focus on progression-free survival (PFS) and overall survival (OS), as well as treatment-related adverse events. From February 2018 to January 2023, 1,604 patients from three institutions were evaluated. Of these, 115 patients received ICI treatment both before and after sCRT (I-sCRT group), while 201 patients received only sCRT, serving as a control group (sCRT group). The inclusion of ICI treatment markedly improved PFS compared to those who received sCRT alone (HR 0.48, 95% CI 0.38–0.61; log-rank p < 0.001). The median PFS was 16.7 months (95% CI 15.5–21.7) in the I-sCRT group versus 9.9 months (95% CI 9.4–11.9) in the sCRT group. OS was also significantly prolonged in I-sCRT group compared to sCRT group, with a median OS of 38.2 months (95% CI 33.2-NA) versus 27.1 months (95% CI 23.3–35.4) (HR 0.64, 95% CI 0.47–0.87; log-rank p = 0.007). The overall safety profile of I-sCRT group was safe and controllable. The propensity score matching results before and after the analysis were consistent. Our analysis revealed a significant improvement in PFS and OS with the combination of ICI treatment administered both before and after sCRT, indicating an effective treatment strategy for patients with unresectable LA-NSCLC. Health sciences/Oncology/Cancer/Lung cancer/Non-small-cell lung cancer Health sciences/Oncology/Cancer/Cancer therapy/Radiotherapy non-small cell lung cancer immune checkpoint inhibitor sequential chemoradiotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Non-small cell lung cancer (NSCLC) is the most prevalent form of cancer and the leading cause of cancer-related mortality worldwide, with approximately 30% of patients diagnosed with locally advanced disease 1 . The standard treatment for medically fit patients with unresectable locally advanced NSCLC (LA-NSCLC) has traditionally consisted of platinum-based chemotherapy combined with radiotherapy, collectively termed chemoradiotherapy (CRT). This approach is administered as either concurrent CRT (cCRT) or sequential CRT (sCRT). Despite this, outcomes remain poor, with a median progression-free survival (PFS) of approximately 8 months and a 5-year survival rate of only 15% 2 . Despite various attempts to improve patient survival by combining different new agents with CRT, results remained disappointing until the PACIFIC trial (NCT02125461) demonstrated that maintenance therapy with the anti-programmed death ligand 1 (anti-PD-L1) agent Durvalumab, administered for up to 12 months following cCRT, significantly improved both overall survival (OS) and progression-free survival (PFS) compared to placebo, with grade ≥ 3 immune-related adverse events occurring in only 15.4% of patients 3 . While cCRT remains the cornerstone of curative-intent treatment for medically fit patients, a significant proportion of these individuals are ineligible due to comorbidities, advanced age, or compromised performance status(PS). International treatment guidelines recommend the use of sCRT as a valid and effective alternative to cCRT for LA-NSCLC, 4 including guidelines from the US National Comprehensive Cancer Network, the European Society for Medical Oncology (ESMO), and the Chinese Society of Clinical Oncology (CSCO) 5 – 7 . The GEMSTONE-301 trial (NCT03728556) demonstrated that Sugemalimab, administered after definitive cCRT or sCRT, could be an effective consolidation therapy for stage III SCLC patients whose disease has not progressed after either treatment modality 8 . The findings from phase 2 PACIFIC-6 trial (NCT03693300) 9 and ongoing PACIFIC-R study (NCT03798535) 10 indicate that immune checkpoint inhibitors (ICIs) following sCRT may represent a reasonable treatment strategy for patients deemed unsuitable for cCRT; the benefits of this approach are further being investigated in the phase 3 PACIFIC-5 trial (NCT03706690). Chemoimmunotherapy represents a paradigm shift in stage IV NSCLC management, offering superior ORR, PFS, and OS compared to chemotherapy alone. These benefits extend across histologic subtypes and PD-L1 expression levels, making it a broadly applicable first-line strategy. Current guidelines (NCCN, ESMO and CSCO) now strongly recommend chemoimmunotherapy for eligible patients without driver mutations 5 . Although chemoimmunotherapy has revolutionized stage IV NSCLC management, its role combined with sCRT in unresectable stage III disease remains unclear. To address this gap, we conducted a multicenter retrospective study comparing the efficacy and toxicity of ICI treatment administered both before and after sCRT versus sCRT alone in unresectable stage III NSCLC patients. 2. Materials and methods 2.1. Study design and patient population This is a multicenter retrospective cohort study, where electronic medical records of stage III NSCLC patients from February 2018 to January 2023 at Shanghai Pulmonary Hospital, Shanghai East Hospital, and Anhui No.2 Provincial People’s Hospital were enrolled. Eligible patients were aged at least 18 years and had histologically or cytologically confirmed locally advanced, unresectable, stage III NSCLC according to the International Association for the Study of Lung Cancer classification, eighth edition. These patients were deemed ineligible for cCRT by the physician based on their comorbidities, advanced age and PS score, and therefore received sequential chemoradiotherapy (sCRT). Patients must have received at least 1 cycle of platinum-based chemotherapy (sCRT group) or immunotherapy combined with chemotherapy (I-sCRT group) and sequentially definitive radiotherapy. Immunotherapy is allowed after radiotherapy in I-sCRT group. Chemotherapy regimens (defined according to local practice) have contained one or more of etoposide, vinorelbine, vinblastine, pemetrexed, taxanes, or gemcitabine, plus cisplatin, carboplatin, or nedaplatin. Radiotherapy had to have reached a total dose of 54–66 Gy, with either the mean dose to the lung not exceeding 15 Gy or the volume of lung parenchyma that received 20 Gy or more not exceeding 30%. For sequential chemoradiotherapy regimens, the interval between the end of a chemotherapy cycle and the initiation of radiotherapy must not have exceeded 42 days. Immunotherapy regimens (defined according to local practice) have contained pembrolizumab, nivolumab, atezolizumab, sugemalimab, camrelizumab, tislelizumab, sintilimab, and toripalimab. Additional inclusion criteria were no disease progression after sequential chemoradiotherapy, an ECOG performance status score of 0 or 2. Patients had to have a life expectancy of at least 12 weeks. Eligible patients also had to have adequate organ function, as assessed by the following laboratory tests (patients must not have received any blood transfusion, erythropoietin, granulocyte colonystimulating factor, or other medical supportive treatment during the 7 days before the experimental drug was given): absolute neutrophil count of 1500 cells per µL or higher; platelet count of 100 000/µL or higher; haemoglobin concentration of 9.0 g/dL or higher; international normalised ratio or prothrombin time of 1.5 × upper limit of normal (ULN) or lower; aspartate aminotransferase and alanine aminotransferase 3 × ULN or less; serum bilirubin 1.5 × ULN or lower (not applicable for patients with Gilbert syndrome); and serum creatinine 1.5 × ULN or lower.Patients were excluded if they had previous exposure to antibodies or other drugs that targeted T-cell co-regulatory proteins (including anti-PD-1 and anti-PD-L1 antibodies); known sensitising EGFR, ALK, or ROS1 gene alterations; active or previous autoimmune disease; evidence of uncontrolled concomitant diseases (eg, uncontrolled congestive heart failure or hypertension) or active infection; unresolved pneumonitis of grade 2 or worse caused by previous chemoradiotherapy; or symptomatic interstitial lung disease. The research received approval from the Institutional Review Boards at each of the three involved hospitals and adhered to the principles of the Declaration of Helsinki, as updated in 2013. All participants provided written consent for their clinical data to be utilized in this study. 2.2. Treatment procedures The specific duration of the ICI treatment in combination with sCRT was determined by the attending clinicians, with no additional selection criteria for patients receiving at least two cycles. Patients without distant metastasis during the induction treatment underwent definitive sCRT with curative intent, which included a prescribed dose of 54–66 Gy of conventional fractionated intensity-modulated radiotherapy and a minimum of two cycles of platinum-based chemotherapy. Those who did not develop distant metastasis during sCRT were eligible to either proceed with consolidation ICI treatment or opt out of treatment. Clinicians tailored the treatment strategy to the specific conditions of each patient. 2.3. Follow-up and data collection Electronic medical records were meticulously reviewed for all included patients. The baseline data collected encompassed gender, age, Eastern Cooperative Oncology Group (ECOG) performance status, smoking history, histology, and tumor staging. Follow-up evaluations post-treatment were scheduled every three months for the first two years and every six months for the subsequent three years. Information on treatment efficacy and toxicity was comprehensively gathered from follow-up visits and imaging reports for the final analyses. Survival data for patients lost to follow-up were considered censored. The last follow-up occurred on Sep. 30, 2024. 2.4. Outcomes The study's primary endpoint was to evaluate the survival benefits of the treatment approach, with a focus on PFS and OS. PFS and OS were measured from the initiation of induction chemotherapy or immunochemotherapy, with PFS defined as the interval from the start of induction therapy to the first occurrence of local-regional progression, distant metastasis, or death. This definition includes disease progression occurring during therapy as well as any post-treatment recurrence. OS was defined as the time from the initiation of treatment until death. The secondary endpoints included the assessment of toxicities. Standardized protocols for monitoring and managing immune-related adverse events were consistently applied across all participating centers. Treatment responses were evaluated based on the Response Evaluation Criteria in Solid Tumors (version 1.1), and toxicities were classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). 2.5. Statistical analysis Demographic and clinical features at baseline were summarized using median values and IQR for continuous variables and proportions for categorical variables. PFS and OS estimates were derived using the Kaplan-Meier method, with median values and their 95% confidence intervals (CIs) calculated, as well as survival probabilities. Cox proportional hazards regression models were employed to investigate the relationship between various relevant variables and survival outcomes. Patients with missing baseline characteristics or treatment data were excluded from the regression analyses. Multivariate analysis included variables with a p-value of less than 0.1 from the univariate analysis. Hazard ratios (HRs) and their 95% CIs were computed, with a two-sided p-value of less than 0.05 considered statistically significant. A propensity score matching (PSM) analysis with a 1:1 ratio was conducted to enhance the comparability of the clinical data between the two groups. Propensity score were established on the following covariates: sex, age, smoking history, ECOG performance status, radiation dose, disease stage, and previous platinum treatment. Data analysis was conducted using SPSS version 23.0 (IBM Corp.) and R programming software (version 4.2.3). 3. Results 3.1. Patient characteristics From February 2018 to January 2023, a total of 1,604 patients with stage III NSCLC from three institutions were evaluated (Fig. 1). Among these patients, 1,153 (71.9%) were excluded based on the following criteria: 427 patients with EGFR mutations, and ALK or ROS1 rearrangements, 369 patients who received cCRT, 322 patients with resectable disease, and 33 patients excluded for other reasons. Ultimately, 451 patients with stage III NSCLC underwent sCRT; of these, 115 patients received ICI treatment both before and after sCRT (I-sCRT group), while 201 patients received only sCRT, serving as a control group for survival and toxicity comparison (sCRT group). The baseline characteristics of the two patient groups are presented in Table 1. Significant differences were not observed in the baseline characteristics across the two patient groups. Of all patients, 102 (88.7%) and 178 (88.6%)were male, 60 (52.2%) and 96 (47.8%) were under 65 years of age, 97 (84.3%) and 169 (84.1%)had a smoking history, and 98 (85.2%) and 171 (85.1%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 while the other were 0. The stages were distributed as follows: 32 (27.8%) and 72 (35.8%) with stage IIIA, 55 (47.8%) and 102 (50.7%) with stage IIIB, and 28 (24.4%) and 27 (13.5%) with stage IIIC. The histological subtypes included squamous cell carcinoma in 68 (59.1%) and 118 (58.7%), Adenocarcinoma in 26 (22.6%) and 43 (21.4%), Not Otherwise Specified in 19 (16.5%) and 24 (11.9%), and Other in 2 (1.8%) and 16 (8.0%) patients. 58 (50.4%) and 79 (39.3%) patients had Programmed death ligand-1 (PD‐L1) expression less than 1%, PD‐L1 expression of more than 1% was found in 21 (18.3%) and 32 (15.9%) patients; and the PD‐L1 status was unknown for 36 (31.3%) and 90 (44.8%) patients, in I-sCRT and sCRT group respectively. 3.2. Treatment outcomes Treatment-related information for all patients is detailed in Table 1. The chemotherapy cycles ranged from 1 to 6, with the vast majority (98, 85.2% and 170, 84.5%) of I-sCRT and sCRT group patients undergoing between 3 and 6 cycles. Specifically, 35 (30.4%) and 58 (28.8%) patients received 3 cycles, 48 (41.7%) and 87 (43.3%) received 4 cycles, 13 (11.3%) and 19 (9.4%) received 5 cycles, and 2 (1.7%) and 6 (3.0%) received 6 cycles of chemotherapy. In both I-sCRT and sCRT group, a higher proportion received carboplatin (85 (73.9%) and 105 (52.2%), respectively) and radiation doses above 60 Gy (93 (80.9%) and 156 (77.6%), respectively). In the I-sCRT cohort, 2 patients (1.7%) achieved a complete response (CR), 88 patients (76.5%) attained a partial response (PR) and 25 patients (21.7%) exhibited stable disease (SD). In contrast, the sCRT cohort saw no patients achieving CR, while 100 patients (49.8%) reached PR and 101 patients (50.2%) presented with SD. 3.3. Survival The median follow-up time was 35 months (range, 4.5 to 65 months). For the entire cohort, the median PFS was 16.7 months (95% CI 15.5–21.7) in the I-sCRT group versus 9.9 months (95% CI 9.4–11.9) in the sCRT group. The inclusion of ICI treatment markedly improved PFS compared to patients who received sCRT alone (HR 0.48, 95% CI 0.38–0.61; log-rank p < 0.001; Fig. 2). In the ICI treatment cohort, PFS rates at 1, 2, and 3 years were 67.6%, 36.6%, and 26.3%, respectively, compared with 41.8%, 13.4% and 7.2% at 1, 2, and 3 years in the sCRT group. OS was also significantly prolonged in patients receiving ICI treatment compared to those who underwent only sCRT, with a median OS of 38.2 months (95% CI 33.2–NA) versus 27.1 months (95% CI 23.3–35.4) (HR 0.64, 95% CI 0.47-0.87; log-rank p = 0.007; Fig. 3). For the I-sCRT group, the 1‐, and 3‐year OS rates were 92.2%, and 54.7%, respectively. In contrast, the sCRT group exhibited 1‐ and 3‐year survival rates of 83.6% and 40.3%, respectively, with the 5‐year survival rate not yet reached within the follow‐up period. PFS and OS were further analyzed and compared across various variables through univariate analysis (Fig. 4). The benefits of PFS and OS with I-sCRT compared with sCRT was observed across nearly all prespecified subgroups. In the I-sCRT group compared to the sCRT group, regardless of whether induction ICI treatment was administered, patients whose disease was classified as SD after sCRT did not seem to benefit in terms of PFS and OS when immunotherapy agents were added in subsequent treatments. Also, no significant benefit in OS was observed in two specific subgroups: female patients and those treated with nedaplatin chemotherapy. 3.4 PSM analysis 111 patients from each group were performing PSM. The median PFS was 16.5 months (95% CI 15.3–21.4) in the I-sCRT group versus 10.3 months (95% CI 9.4–13.0) in the sCRT group. The inclusion of ICI treatment markedly improved PFS compared to patients who received sCRT alone (HR 0.52, 95% CI 0.39–0.69; log-rank p < 0.001; Fig. 5). OS was still significantly prolonged in patients receiving ICI treatment compared to those who underwent only sCRT, with a median OS of 38.2 months (95% CI 33.2–NA) versus 26.1 months (95% CI 20.3–39.5) (HR 0.65, 95% CI 0.45-0.94; log-rank p = 0.022; Fig. 6). PFS and OS were further analyzed and compared across various variables through univariate analysis (Fig. 7). 3.5 Safety The comparison of treatment-related toxicities between patients who underwent ICI treatment combined with sCRT and those who received sCRT alone was presented in Table 2. In the I-sCRT group, the incidence rates of grade 1–2, 3–4, and 5 pneumonitis, attributed to various causes including radiation pneumonitis (RP), immune-related pneumonitis, and infections from diverse pathogens, were 30.4%, 5.2%, and 0.9%, respectively, compared to 28.4%, 4.0%, and 0.0% in the sCRT group, revealing no significant differences. One patient in the I-sCRT group died from immune‐related pneumonitis during ICI consolidation treatment, and the cause of death was determined to be complicated by severe bacterial lung infection based on chest CT analysis. While no patient in the sCRT group died from RP. All other patients diagnosed with pneumonia fully recovered after treatment with oral or intravenous corticosteroids and additional supportive therapies. Generally, most of the treatment‐related toxicities in both groups were mild, predominantly classified as grades 1–2. ICI treatment only led to a marginal significant statistical increase in abnormal thyroid function (hypothyroidism and hyperthyroidism) and hyperlipidemia, common adverse events of ICI treatment that are relatively manageable in clinical settings. Other toxicities showed no significant differences between the two groups. Among patients who received ICI treatment, fatigue was the most common grade 1–2 toxicities (45.2%), followed by leukopenia (43.5%) and radiation esophagitis (40.9%). The most frequent severe (grade ≥ 3) adverse events were hematologic toxicities, including leukopenia (10.4%), decreased platelet count (8.7%) and anemia (4.3%), followed by pneumonitis (5.2%). 4. Discussion Our study demonstrates that the incidence of treatment-related adverse events in the I-sCRT group is within an acceptable range, which confirming that the combination of ICI treatment and chemotherapy does not significantly increase the risk of adverse events in patients. To our knowledge, this multicenter retrospective study we conducted represents the largest investigation to date of the efficacy and safety of ICI treatment combined with definitive sCRT in patients with unresectable LA-NSCLC. The outcomes of this innovative treatment approach are encouraging, as indicated by a median PFS of 16.7 months and a median OS of 38.2 months. After performing PSM, the median PFS and OS still show significant statistical differences. Importantly, while severe adverse events were predominantly hematological, the overall treatment was well tolerated, thereby underscoring its favorable safety profile. Updated analyses from the phase III PACIFIC trial demonstrated that 42.9% of patients randomized to durvalumab remained alive at 5 years, with 33.1% maintaining progression-free survival. While cCRT showed superior survival outcomes compared to sCRT in unresectable LA-NSCLC patients—attributable to enhanced locoregional control —this benefit came with increased yet manageable acute esophageal toxicity. Real-world evidence reveals substantial treatment intolerance to cCRT, particularly among older adults (≥ 65 years) and patients with ECOG performance status ≥ 2, leading to sCRT becoming the preferred regimen in these subgroups 11 . Supporting this trend, a real-world study found older LA-NSCLC patients were significantly more likely to receive radiotherapy alone (40.1%) or sCRT (33.3%) than cCRT (26.6%) 12,13 . The GEMSTONE-301 trial has established sugemalimab as an effective consolidation therapy for unresectable LA-NSCLC patients without disease progression after sCRT or cCRT. Notably, in the sCRT subgroup, sugemalimab demonstrated significantly prolonged progression-free survival (PFS) (8.08 vs. 4.07 months; P < 0.001) 8 . Supporting these findings, the PACIFIC-6 study revealed that durvalumab post-sCRT exhibited a safety profile consistent with the pivotal PACIFIC trial, with grade ≥ 3 AEs occurring in 18.8% of patients. Importantly, only 1.7% experienced grade 5 AEs, predominantly pneumonitis (2 cases). While the single-arm design precludes definitive efficacy conclusions, the observed median PFS of 10.9 months and 12-month OS rate of 84.1% are clinically encouraging 9 . Emerging evidence from PACIFIC-R real-world data further validates this approach, showing 3-year overall survival rates approaching 60% in sCRT-treated patients receiving durvalumab consolidation. Additionally, retrospective multicenter studies demonstrate comparable survival benefits between cCRT and sCRT subgroups when combined with durvalumab maintenance (PFS : 11.0 vs. 5.4 months; HR = 0.75) 10 . The ongoing PACIFIC-5 phase III trial is prospectively evaluating durvalumab in sCRT populations, with interim analyses already indicating clinically meaningful PFS improvements. Collectively, these data strongly support the integration of immune checkpoint inhibitors (ICIs) with sCRT as a standard-of-care for unresectable LA-NSCLC, particularly in patients intolerant to cCRT. Concurrent chemoradioimmunotherapy accelerates objective tumor response (shrinkage) and prolongs response duration. Robust evidence supports ICIs integration with CRT, as exemplified by the PACIFIC trial which achieved a 12-month duration of response (DoR) rate of 72.8%—surpassed in the KEYNOTE-799 trial (NCT03631784, cohort A: 79.7%; cohort B: 75.6%) 14 . The Phase II APOLO study (NCT04131521) implemented a neoadjuvant regimen: atezolizumab + chemotherapy → CCRT → atezolizumab consolidation. This approach yielded 12-month PFS rates of 68.4% (intention-to-treat, ITT) and 78.1% (per-protocol, PP), with corresponding OS rates of 86.8% and 90.6% 15 . Considering that the combination of immunotherapy and chemotherapy has a better objective response rate (ORR), which can facilitate better surgery or radiotherapy, some clinical experts have already begun to try using it in the clinical practice of locally advanced lung cancer. Safety analyses reveal ICI-specific toxicity patterns. The NICOLAS trial (NCT03628521) documented Grade ≥ 3 pneumonitis in 11.7% (9/77) of nivolumab-treated patients, including one fatal event (Grade 5). Notably, 4 cases were radiation-attributable TRT 16 . Similarly, the DETERRED trial (NCT03818776) reported Grade ≥ 3 immune-related toxicities in 20% (6/30) with cCRT 17 . KEYNOTE-799 observed 7.4% (16/216) Grade ≥ 3 pneumonitis, including 2.3% (5/216) fatalities. Atezolizumab-based regimens showed 27.4% (17/62) Grade ≥ 3 immune-related AEs and 48.4% (30/62) treatment-related AEs, mirroring PACIFIC trial safety data with durvalumab 14 . These findings underscore the necessity for risk-adapted monitoring protocols when combining ICIs with CRT. In real-world clinical practice, various factors may prevent every patient with unresectable stage III NSCLC from receiving the standard treatment regimens 18 . A substantial subset of patients with potentially resectable stage III SCLC remain ineligible to undergo surgery following assessment after neo-adjuvant chemotherapy combined with immunotherapy. As a result, they often transition to radical radiotherapy followed by consolidating ICI. Furthermore, a significant proportion of patients with unresectable locally advanced disease present with large radiotherapy target volumes. After completing the planned chemotherapy and immunotherapy, these lesions may shrink, thereby providing the opportunity for subsequent radiotherapy. For the younger patient population, the treatment-related toxicities associated with chemotherapy combined with immunotherapy are deemed tolerable when weighed against the benefits of the treatment's efficacy. In clinical practice, the availability of immunotherapeutic agents and radiotherapy equipment, including limited availability in primary hospitals, as well as economic considerations, such as the coverage of medications by health insurance, also should be comprehensively evaluated. These factors have resulted in a significant proportion of patients in the real world adopting a treatment regimen involving chemotherapy combined with immunotherapy, followed by sequential radiotherapy and subsequent immunotherapy consolidation. Building upon the PACIFIC and GEMSTONE-301 trial paradigms, in addition to the combinations of various chemotherapy, radiotherapy, and immunotherapy strategies that we just mentioned, the treatment paradigm for unresectable LA-NSCLC is continually evolving. As LAURA trail reported, treatment with EGFR tyrosine kinase inhibitor (TKI) osimertinib resulted in significantly longer PFS than placebo in patients with unresectable stage III EGFR-mutated NSCLC, demonstrating a mPFS of 39.1 vs. 5.6 months (HR 0.16, 95% CI 0.10–0.25; p < 0.0001) 19 . Patients with ALK-positive LA-NSCLC significantly improved rwPFS when treated with consolidation ALK-TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK-TKI therapy and durvalumab demonstrate an improvement in OS compared to observation alone, ALK-TKI therapy appears to be the superior option, highlighting its critical role in enhancing patient survival 20 . In another prospective study (SPRINT), treatment with induction pembrolizumab, risk-adapted thoracic radiotherapy without chemotherapy, and additional pembrolizumab produced promising safety and efficacy outcomes for patients with LA-NSCLC exhibiting high PD-L1 expression (TPS 50%). Approximately half of the patients demonstrated a response to three cycles of induction pembrolizumab, resulting in a 1-year PFS rate of 76% and OS rates of 92% and 76% at 1 and 2 years, respectively 21 . All these results are encouraging and may be incorporated into treatment guidelines for specific subgroups of LA-NSCLC patients in the future, including the elderly, those with high PD-L1 expression, and patients harboring genetic mutations. This study demonstrates two key strengths. First, by systematically documenting the actual implementation rate of sCRT in clinical practice (55.0% vs. 45.0% in the cCRT population), it addresses the rigid treatment sequencing constraints typically encountered in traditional RCTs. Our real-world data collection preserves the clinical diversity in treatment decision-making, which is influenced by factors such as patient performance status and tumor response, thus providing direct evidence for evaluating the effectiveness of sequential therapy under real-world conditions. Second, our study encompasses three centers nationwide with a total of 1,604 cases, significantly surpassing previous multicenter investigations (e.g., 564 cases in the GEMSTONE-301 study 8 ). Standardized data collection protocols, complemented by dual-entry verification, ensured comprehensive documentation of inter-institutional therapeutic variations (e.g., radiation fraction schemes and chemotherapy intervals), thereby enriching the interpretation of clinical contexts. This study acknowledges several limitations. First, as a retrospective investigation, its retrospective nature design may introduce confounding factors that can affect the evaluation of treatment efficacy. Second, there are issues of standardization in therapeutic protocols; the use of various ICIs—each with different half-lives and immune-related adverse event profiles—coupled with potential technical variations in linear accelerators and radiotherapy planning systems across institutions, which result in deviations from uniform dosing. Third, population specificity must be considered, as significant differences exist between Asian and Caucasian populations regarding immune checkpoint gene polymorphisms and tumor mutational burden thresholds, highlighting the need for further validation in non-Asian cohorts. Fourth, the systematic application of advanced evaluation modalities, such as PET-CT, was lacking, which may increase the risk of misdiagnosis related to pseudo-progression specific to immunotherapy (observed in 4%-10% of cases). The applicability of RECIST criteria in combined therapy settings is also limited, particularly since post-radiotherapy localized inflammatory responses may interfere with imaging assessments. Lastly, at baseline, the tumor PD-L1 expression was not available in more than one-third of the patients (n = 36, 31.3%, and 90, 44.8%, respectively in I-sCRT and sCRT group). Future global multicenter prospective studies should incorporate standardized radiotherapy parameters, stratified analyses of ICI agents, and comparative cohorts across different ethnicities, thereby enhancing the reliability and generalizability of the evidence. 5. Conclusion The analysis of this multicenter retrospective study showed a significant and clinically meaningful improvement in PFS and OS with the combination of ICI treatment before and after sCRT, which presents an effective and manageable treatment approach for patients with locally advanced, unresectable, stage III NSCLC without disease progression after chemoradiotherapy. We anticipate the results of future prospective studies to further validate this treatment approach. Declarations Conflict of interest statement The authors indicated no potential conflicts of interest. Acknowledgements This study was partially supported by CSCO - HANSOH Cancer Research Fund - Key Project (Subject No: Y-HS202102-0199), Shanghai Hospital Development Center Technical Specification Management and Promotion Project (Subject No: SHDC22024219). The study was approved by Ethics Committee of Shanghai Pulmonary Hospital (No. 19231ZL-1). The institutional review board at each center approved the study’s protocol. Written informed consent was taken from all the patients. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). References Siegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H. & Jemal, A. Cancer statistics, 2025. CA Cancer J Clin 75, 10–45 (2025). https://doi.org/10.3322/caac.21871 Auperin, A. et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 28, 2181–2190 (2010). https://doi.org/10.1200/JCO.2009.26.2543 Faivre-Finn, C. et al. Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-an Update From the PACIFIC Trial. J Thorac Oncol 16, 860–867 (2021). https://doi.org/10.1016/j.jtho.2020.12.015 Walraven, I. et al. Treatment Variation of Sequential versus Concurrent Chemoradiotherapy in Stage III Non-Small Cell Lung Cancer Patients in the Netherlands and Belgium. 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Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 23, 209–219 (2022). https://doi.org/10.1016/S1470-2045(21)00630-6 Zhao, B., Li, H., Wu, J. & Ma, W. Durvalumab After Sequential Chemoradiotherapy Is Safe for Stage III, Unresectable NSCLC: Results From Phase 2 PACIFIC-6 Trial. J Thorac Oncol 18, e1–e2 (2023). https://doi.org/10.1016/j.jtho.2022.09.002 Girard, N. et al. Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study. J Thorac Oncol 18, 181–193 (2023). https://doi.org/10.1016/j.jtho.2022.10.003 Spigel, D. R. et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol 40, 1301–1311 (2022). https://doi.org/10.1200/JCO.21.01308 Bruni, A. et al. A Real-World, Multicenter, Observational Retrospective Study of Durvalumab After Concomitant or Sequential Chemoradiation for Unresectable Stage III Non-Small Cell Lung Cancer. Front Oncol 11, 744956 (2021). https://doi.org/10.3389/fonc.2021.744956 Verschueren, M. V. et al. Durvalumab after chemoradiotherapy in patients with stage III non-small-cell lung cancer: real-world outcomes versus clinical trial results. Immunotherapy 15, 839–851 (2023). https://doi.org/10.2217/imt-2023-0002 Jabbour, S. K. et al. Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. JAMA Oncol 7, 1–9 (2021). https://doi.org/10.1001/jamaoncol.2021.2301 Provencio, M. et al. OA12.05 APOLO: Phase II Trial of Induction Chemo-Immunotherapy Plus Chemoradiotherapy and Maintenance Immunotherapy in Stage III NSCLC. Journal of Thoracic Oncology 19, S37 (2024). https://doi.org/10.1016/j.jtho.2024.09.067 Peters, S. et al. Progression-Free and Overall Survival for Concurrent Nivolumab With Standard Concurrent Chemoradiotherapy in Locally Advanced Stage IIIA-B NSCLC: Results From the European Thoracic Oncology Platform NICOLAS Phase II Trial (European Thoracic Oncology Platform 6–14). J Thorac Oncol 16, 278–288 (2021). https://doi.org/10.1016/j.jtho.2020.10.129 Lin, S. H. et al. Phase II Trial of Concurrent Atezolizumab With Chemoradiation for Unresectable NSCLC. J Thorac Oncol 15, 248–257 (2020). https://doi.org/10.1016/j.jtho.2019.10.024 Hung, A. et al. Chemoradiation treatment patterns among United States Veteran Health Administration patients with unresectable stage III non-small cell lung cancer. BMC Cancer 21, 824 (2021). https://doi.org/10.1186/s12885-021-08577-y Lu, S. et al. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med 391, 585–597 (2024). https://doi.org/10.1056/NEJMoa2402614 Nassar, A. H. et al. Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC. J Thorac Oncol 20, 109–118 (2025). https://doi.org/10.1016/j.jtho.2024.09.1379 Ohri, N. et al. Selective Personalized RadioImmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial (SPRINT). J Clin Oncol 42, 562–570 (2024). https://doi.org/10.1200/JCO.23.00627 Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files T1.docx Table 1. Baseline characteristics of patients T2.docx Table 2. Treatment-related adverse events Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8849122","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":607172911,"identity":"a3c64567-38c7-4c65-a6a0-26a4b01d8d61","order_by":0,"name":"Qinghua Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYDACZjACAvYGEMnGAyQMiNTCc5hYLQwwLRLJcAH8WviO8x5+Xdhml7jh5vuDjwt+8ckwsDdvk2CouYNTi+RhvjTrmW3Jxga3k5mNZ/YBHcZzrEyC4dgznFoMDvOYGfO2McsBtbBJ8/YAtUjkmEkwNhwmpKWex+DmYagW+TcEtRg/5m07LGdwg5lNmucHyBYe/FokgbYw85w7bix5JtnYmLeBjYeNJ63YIuEYbi18588Yf+Ypq07sO37w4WOeP8fs+dkPb7zxoQa3FoYDDGwScA5j2zEGNhAjAbcGkBbmDwjenxp8akfBKBgFo2CEAgDt20qbYHbXWAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0005-7487-6018","institution":"Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University","correspondingAuthor":true,"prefix":"","firstName":"Qinghua","middleName":"","lastName":"Xu","suffix":""},{"id":607172912,"identity":"be3c3c58-1c2d-4dcc-a0b1-0d5bf441d54b","order_by":1,"name":"Xiaoshuai Yuan","email":"","orcid":"","institution":"Shanghai Pulmonary Hospital, School of Medicine, Tongji University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoshuai","middleName":"","lastName":"Yuan","suffix":""},{"id":607172913,"identity":"49584bd7-6312-435f-bb6b-a128a00e06ef","order_by":2,"name":"Shuyan Meng","email":"","orcid":"","institution":"Shanghai Pulmonary Hospital, School of Medicine, Tongji University","correspondingAuthor":false,"prefix":"","firstName":"Shuyan","middleName":"","lastName":"Meng","suffix":""},{"id":607172914,"identity":"52b7b6d3-5974-4d4d-b900-889a00082784","order_by":3,"name":"Guanghui Gao","email":"","orcid":"","institution":"Shanghai Pulmonary Hospital, School of Medicine, Tongji University","correspondingAuthor":false,"prefix":"","firstName":"Guanghui","middleName":"","lastName":"Gao","suffix":""},{"id":607172915,"identity":"a1403dfc-0ac1-4011-bb9a-fd9fc94189c2","order_by":4,"name":"Chenglong 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08:37:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8849122/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8849122/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104996347,"identity":"d66a4079-1e51-4228-9748-8326dc179a09","added_by":"auto","created_at":"2026-03-19 16:12:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":143076,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient cohort\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/df97fcfff0466becb046e118.png"},{"id":104996352,"identity":"bfdcd5c8-2600-4bfc-852f-cbc5d8fa204d","added_by":"auto","created_at":"2026-03-19 16:12:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":642293,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of progression-free survival\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/83fed41c06b33e21a73c2b02.png"},{"id":104996355,"identity":"195ebde6-9a76-4e50-b32b-c892a4daca64","added_by":"auto","created_at":"2026-03-19 16:12:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":649391,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of overall survival\u003c/p\u003e","description":"","filename":"F3.png","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/1673d06863bb8f35519e6dd0.png"},{"id":104996351,"identity":"8e23b3a7-422a-48d6-83c2-05b3e98715fd","added_by":"auto","created_at":"2026-03-19 16:12:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":527130,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of progression-free survival and overall survival\u003c/p\u003e","description":"","filename":"F4.png","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/6e3b20eee9277cbc065e0217.png"},{"id":105035605,"identity":"1fb77dbb-3cb0-449d-96c8-0edb194704c2","added_by":"auto","created_at":"2026-03-20 07:26:19","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":516474,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of progression-free survival in propensity score-matched patients\u003c/p\u003e","description":"","filename":"F5.png","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/f6067afb65f5e4ff7eef3e40.png"},{"id":104996349,"identity":"a267daeb-dac4-43d0-b611-188dbb351626","added_by":"auto","created_at":"2026-03-19 16:12:30","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":521058,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of overall survival in propensity score-matched patients\u003c/p\u003e","description":"","filename":"F6.png","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/e67cfaed25bea3697325ecad.png"},{"id":105035713,"identity":"475a080c-6f7b-482c-9da5-b2d25459ce28","added_by":"auto","created_at":"2026-03-20 07:26:30","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":391240,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of progression-free survival and overall survival in propensity score-matched patients\u003c/p\u003e","description":"","filename":"F7.png","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/0cd852b528debb377eb60780.png"},{"id":105036835,"identity":"183bdedb-322e-4e7b-be89-3edd776801cb","added_by":"auto","created_at":"2026-03-20 07:36:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3470198,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/d681bb40-bb2d-4bb2-8907-111fa6e54968.pdf"},{"id":104996346,"identity":"84d670b7-0d8e-44de-91ee-4e281c4b52b6","added_by":"auto","created_at":"2026-03-19 16:12:30","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19672,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. Baseline characteristics of patients\u003c/p\u003e","description":"","filename":"T1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/314c88cdf4c583a84a011c0e.docx"},{"id":104996353,"identity":"4244cbfd-b35d-41db-9dd6-f45b5eb8fece","added_by":"auto","created_at":"2026-03-19 16:12:30","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18163,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2. Treatment-related adverse events\u003c/p\u003e","description":"","filename":"T2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8849122/v1/d5f75e401577bc7ae244a5c2.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Sequential Chemoradiotherapy Combined with Immunotherapy Versus Sequential Chemoradiotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: A Multicenter Retrospective Cohort Study with Propensity Score Matching","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eNon-small cell lung cancer (NSCLC) is the most prevalent form of cancer and the leading cause of cancer-related mortality worldwide, with approximately 30% of patients diagnosed with locally advanced disease\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The standard treatment for medically fit patients with unresectable locally advanced NSCLC (LA-NSCLC) has traditionally consisted of platinum-based chemotherapy combined with radiotherapy, collectively termed chemoradiotherapy (CRT). This approach is administered as either concurrent CRT (cCRT) or sequential CRT (sCRT). Despite this, outcomes remain poor, with a median progression-free survival (PFS) of approximately 8 months and a 5-year survival rate of only 15%\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite various attempts to improve patient survival by combining different new agents with CRT, results remained disappointing until the PACIFIC trial (NCT02125461) demonstrated that maintenance therapy with the anti-programmed death ligand 1 (anti-PD-L1) agent Durvalumab, administered for up to 12 months following cCRT, significantly improved both overall survival (OS) and progression-free survival (PFS) compared to placebo, with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 immune-related adverse events occurring in only 15.4% of patients\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhile cCRT remains the cornerstone of curative-intent treatment for medically fit patients, a significant proportion of these individuals are ineligible due to comorbidities, advanced age, or compromised performance status(PS). International treatment guidelines recommend the use of sCRT as a valid and effective alternative to cCRT for LA-NSCLC,\u003csup\u003e4\u003c/sup\u003e including guidelines from the US National Comprehensive Cancer Network, the European Society for Medical Oncology (ESMO), and the Chinese Society of Clinical Oncology (CSCO)\u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The GEMSTONE-301 trial (NCT03728556) demonstrated that Sugemalimab, administered after definitive cCRT or sCRT, could be an effective consolidation therapy for stage III SCLC patients whose disease has not progressed after either treatment modality\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The findings from phase 2 PACIFIC-6 trial (NCT03693300)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and ongoing PACIFIC-R study (NCT03798535)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e indicate that immune checkpoint inhibitors (ICIs) following sCRT may represent a reasonable treatment strategy for patients deemed unsuitable for cCRT; the benefits of this approach are further being investigated in the phase 3 PACIFIC-5 trial (NCT03706690).\u003c/p\u003e \u003cp\u003eChemoimmunotherapy represents a paradigm shift in stage IV NSCLC management, offering superior ORR, PFS, and OS compared to chemotherapy alone. These benefits extend across histologic subtypes and PD-L1 expression levels, making it a broadly applicable first-line strategy. Current guidelines (NCCN, ESMO and CSCO) now strongly recommend chemoimmunotherapy for eligible patients without driver mutations\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Although chemoimmunotherapy has revolutionized stage IV NSCLC management, its role combined with sCRT in unresectable stage III disease remains unclear. To address this gap, we conducted a multicenter retrospective study comparing the efficacy and toxicity of ICI treatment administered both before and after sCRT versus sCRT alone in unresectable stage III NSCLC patients.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study design and patient population\u003c/h2\u003e \u003cp\u003eThis is a multicenter retrospective cohort study, where electronic medical records of stage III NSCLC patients from February 2018 to January 2023 at Shanghai Pulmonary Hospital, Shanghai East Hospital, and Anhui No.2 Provincial People\u0026rsquo;s Hospital were enrolled. Eligible patients were aged at least 18 years and had histologically or cytologically confirmed locally advanced, unresectable, stage III NSCLC according to the International Association for the Study of Lung Cancer classification, eighth edition.\u003c/p\u003e \u003cp\u003eThese patients were deemed ineligible for cCRT by the physician based on their comorbidities, advanced age and PS score, and therefore received sequential chemoradiotherapy (sCRT). Patients must have received at least 1 cycle of platinum-based chemotherapy (sCRT group) or immunotherapy combined with chemotherapy (I-sCRT group) and sequentially definitive radiotherapy. Immunotherapy is allowed after radiotherapy in I-sCRT group. Chemotherapy regimens (defined according to local practice) have contained one or more of etoposide, vinorelbine, vinblastine, pemetrexed, taxanes, or gemcitabine, plus cisplatin, carboplatin, or nedaplatin. Radiotherapy had to have reached a total dose of 54\u0026ndash;66 Gy, with either the mean dose to the lung not exceeding 15 Gy or the volume of lung parenchyma that received 20 Gy or more not exceeding 30%. For sequential chemoradiotherapy regimens, the interval between the end of a chemotherapy cycle and the initiation of radiotherapy must not have exceeded 42 days. Immunotherapy regimens (defined according to local practice) have contained pembrolizumab, nivolumab, atezolizumab, sugemalimab, camrelizumab, tislelizumab, sintilimab, and toripalimab.\u003c/p\u003e \u003cp\u003eAdditional inclusion criteria were no disease progression after sequential chemoradiotherapy, an ECOG performance status score of 0 or 2. Patients had to have a life expectancy of at least 12 weeks. Eligible patients also had to have adequate organ function, as assessed by the following laboratory tests (patients must not have received any blood transfusion, erythropoietin, granulocyte colonystimulating factor, or other medical supportive treatment during the 7 days before the experimental drug was given): absolute neutrophil count of 1500 cells per \u0026micro;L or higher; platelet count of 100 000/\u0026micro;L or higher; haemoglobin concentration of 9.0 g/dL or higher; international normalised ratio or prothrombin time of 1.5 \u0026times; upper limit of normal (ULN) or lower; aspartate aminotransferase and alanine aminotransferase 3 \u0026times; ULN or less; serum bilirubin 1.5 \u0026times; ULN or lower (not applicable for patients with Gilbert syndrome); and serum creatinine 1.5 \u0026times; ULN or lower.Patients were excluded if they had previous exposure to antibodies or other drugs that targeted T-cell co-regulatory proteins (including anti-PD-1 and anti-PD-L1 antibodies); known sensitising EGFR, ALK, or ROS1 gene alterations; active or previous autoimmune disease; evidence of uncontrolled concomitant diseases (eg, uncontrolled congestive heart failure or hypertension) or active infection; unresolved pneumonitis of grade 2 or worse caused by previous chemoradiotherapy; or symptomatic interstitial lung disease. The research received approval from the Institutional Review Boards at each of the three involved hospitals and adhered to the principles of the Declaration of Helsinki, as updated in 2013. All participants provided written consent for their clinical data to be utilized in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Treatment procedures\u003c/h2\u003e \u003cp\u003eThe specific duration of the ICI treatment in combination with sCRT was determined by the attending clinicians, with no additional selection criteria for patients receiving at least two cycles. Patients without distant metastasis during the induction treatment underwent definitive sCRT with curative intent, which included a prescribed dose of 54\u0026ndash;66 Gy of conventional fractionated intensity-modulated radiotherapy and a minimum of two cycles of platinum-based chemotherapy. Those who did not develop distant metastasis during sCRT were eligible to either proceed with consolidation ICI treatment or opt out of treatment. Clinicians tailored the treatment strategy to the specific conditions of each patient.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Follow-up and data collection\u003c/h2\u003e \u003cp\u003eElectronic medical records were meticulously reviewed for all included patients. The baseline data collected encompassed gender, age, Eastern Cooperative Oncology Group (ECOG) performance status, smoking history, histology, and tumor staging. Follow-up evaluations post-treatment were scheduled every three months for the first two years and every six months for the subsequent three years. Information on treatment efficacy and toxicity was comprehensively gathered from follow-up visits and imaging reports for the final analyses. Survival data for patients lost to follow-up were considered censored. The last follow-up occurred on Sep. 30, 2024.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Outcomes\u003c/h2\u003e \u003cp\u003eThe study's primary endpoint was to evaluate the survival benefits of the treatment approach, with a focus on PFS and OS. PFS and OS were measured from the initiation of induction chemotherapy or immunochemotherapy, with PFS defined as the interval from the start of induction therapy to the first occurrence of local-regional progression, distant metastasis, or death. This definition includes disease progression occurring during therapy as well as any post-treatment recurrence. OS was defined as the time from the initiation of treatment until death. The secondary endpoints included the assessment of toxicities. Standardized protocols for monitoring and managing immune-related adverse events were consistently applied across all participating centers. Treatment responses were evaluated based on the Response Evaluation Criteria in Solid Tumors (version 1.1), and toxicities were classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Statistical analysis\u003c/h2\u003e \u003cp\u003eDemographic and clinical features at baseline were summarized using median values and IQR for continuous variables and proportions for categorical variables. PFS and OS estimates were derived using the Kaplan-Meier method, with median values and their 95% confidence intervals (CIs) calculated, as well as survival probabilities. Cox proportional hazards regression models were employed to investigate the relationship between various relevant variables and survival outcomes. Patients with missing baseline characteristics or treatment data were excluded from the regression analyses. Multivariate analysis included variables with a p-value of less than 0.1 from the univariate analysis. Hazard ratios (HRs) and their 95% CIs were computed, with a two-sided p-value of less than 0.05 considered statistically significant. A propensity score matching (PSM) analysis with a 1:1 ratio was conducted to enhance the comparability of the clinical data between the two groups. Propensity score were established on the following covariates: sex, age, smoking history, ECOG performance status, radiation dose, disease stage, and previous platinum treatment. Data analysis was conducted using SPSS version 23.0 (IBM Corp.) and R programming software (version 4.2.3).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Patient characteristics\u003c/h2\u003e \u003cp\u003eFrom February 2018 to January 2023, a total of 1,604 patients with stage III NSCLC from three institutions were evaluated (Fig.\u0026nbsp;1). Among these patients, 1,153 (71.9%) were excluded based on the following criteria: 427 patients with EGFR mutations, and ALK or ROS1 rearrangements, 369 patients who received cCRT, 322 patients with resectable disease, and 33 patients excluded for other reasons. Ultimately, 451 patients with stage III NSCLC underwent sCRT; of these, 115 patients received ICI treatment both before and after sCRT (I-sCRT group), while 201 patients received only sCRT, serving as a control group for survival and toxicity comparison (sCRT group). The baseline characteristics of the two patient groups are presented in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eSignificant differences were not observed in the baseline characteristics across the two patient groups. Of all patients, 102 (88.7%) and 178 (88.6%)were male, 60 (52.2%) and 96 (47.8%) were under 65 years of age, 97 (84.3%) and 169 (84.1%)had a smoking history, and 98 (85.2%) and 171 (85.1%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 while the other were 0. The stages were distributed as follows: 32 (27.8%) and 72 (35.8%) with stage IIIA, 55 (47.8%) and 102 (50.7%) with stage IIIB, and 28 (24.4%) and 27 (13.5%) with stage IIIC. The histological subtypes included squamous cell carcinoma in 68 (59.1%) and 118 (58.7%), Adenocarcinoma in 26 (22.6%) and 43 (21.4%), Not Otherwise Specified in 19 (16.5%) and 24 (11.9%), and Other in 2 (1.8%) and 16 (8.0%) patients. 58 (50.4%) and 79 (39.3%) patients had Programmed death ligand-1 (PD‐L1) expression less than 1%, PD‐L1 expression of more than 1% was found in 21 (18.3%) and 32 (15.9%) patients; and the PD‐L1 status was unknown for 36 (31.3%) and 90 (44.8%) patients, in I-sCRT and sCRT group respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Treatment outcomes\u003c/h2\u003e \u003cp\u003eTreatment-related information for all patients is detailed in Table\u0026nbsp;1. The chemotherapy cycles ranged from 1 to 6, with the vast majority (98, 85.2% and 170, 84.5%) of I-sCRT and sCRT group patients undergoing between 3 and 6 cycles. Specifically, 35 (30.4%) and 58 (28.8%) patients received 3 cycles, 48 (41.7%) and 87 (43.3%) received 4 cycles, 13 (11.3%) and 19 (9.4%) received 5 cycles, and 2 (1.7%) and 6 (3.0%) received 6 cycles of chemotherapy. In both I-sCRT and sCRT group, a higher proportion received carboplatin (85 (73.9%) and 105 (52.2%), respectively) and radiation doses above 60 Gy (93 (80.9%) and 156 (77.6%), respectively).\u003c/p\u003e \u003cp\u003eIn the I-sCRT cohort, 2 patients (1.7%) achieved a complete response (CR), 88 patients (76.5%) attained a partial response (PR) and 25 patients (21.7%) exhibited stable disease (SD). In contrast, the sCRT cohort saw no patients achieving CR, while 100 patients (49.8%) reached PR and 101 patients (50.2%) presented with SD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Survival\u003c/h2\u003e \u003cp\u003eThe median follow-up time was 35 months (range, 4.5 to 65 months). For the entire cohort, the median PFS was 16.7 months (95% CI 15.5\u0026ndash;21.7) in the I-sCRT group versus 9.9 months (95% CI 9.4\u0026ndash;11.9) in the sCRT group. The inclusion of ICI treatment markedly improved PFS compared to patients who received sCRT alone (HR 0.48, 95% CI 0.38\u0026ndash;0.61; log-rank p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;2). In the ICI treatment cohort, PFS rates at 1, 2, and 3 years were 67.6%, 36.6%, and 26.3%, respectively, compared with 41.8%, 13.4% and 7.2% at 1, 2, and 3 years in the sCRT group. OS was also significantly prolonged in patients receiving ICI treatment compared to those who underwent only sCRT, with a median OS of 38.2 months (95% CI 33.2\u0026ndash;NA) versus 27.1 months (95% CI 23.3\u0026ndash;35.4) (HR 0.64, 95% CI 0.47-0.87; log-rank p\u0026thinsp;=\u0026thinsp;0.007; Fig.\u0026nbsp;3). For the I-sCRT group, the 1‐, and 3‐year OS rates were 92.2%, and 54.7%, respectively. In contrast, the sCRT group exhibited 1‐ and 3‐year survival rates of 83.6% and 40.3%, respectively, with the 5‐year survival rate not yet reached within the follow‐up period.\u003c/p\u003e \u003cp\u003ePFS and OS were further analyzed and compared across various variables through univariate analysis (Fig.\u0026nbsp;4). The benefits of PFS and OS with I-sCRT compared with sCRT was observed across nearly all prespecified subgroups. In the I-sCRT group compared to the sCRT group, regardless of whether induction ICI treatment was administered, patients whose disease was classified as SD after sCRT did not seem to benefit in terms of PFS and OS when immunotherapy agents were added in subsequent treatments. Also, no significant benefit in OS was observed in two specific subgroups: female patients and those treated with nedaplatin chemotherapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4 PSM analysis\u003c/h2\u003e \u003cp\u003e111 patients from each group were performing PSM. The median PFS was 16.5 months (95% CI 15.3\u0026ndash;21.4) in the I-sCRT group versus 10.3 months (95% CI 9.4\u0026ndash;13.0) in the sCRT group. The inclusion of ICI treatment markedly improved PFS compared to patients who received sCRT alone (HR 0.52, 95% CI 0.39\u0026ndash;0.69; log-rank p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;5). OS was still significantly prolonged in patients receiving ICI treatment compared to those who underwent only sCRT, with a median OS of 38.2 months (95% CI 33.2\u0026ndash;NA) versus 26.1 months (95% CI 20.3\u0026ndash;39.5) (HR 0.65, 95% CI 0.45-0.94; log-rank p\u0026thinsp;=\u0026thinsp;0.022; Fig.\u0026nbsp;6). PFS and OS were further analyzed and compared across various variables through univariate analysis (Fig.\u0026nbsp;7).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Safety\u003c/h2\u003e \u003cp\u003eThe comparison of treatment-related toxicities between patients who underwent ICI treatment combined with sCRT and those who received sCRT alone was presented in Table\u0026nbsp;2. In the I-sCRT group, the incidence rates of grade 1\u0026ndash;2, 3\u0026ndash;4, and 5 pneumonitis, attributed to various causes including radiation pneumonitis (RP), immune-related pneumonitis, and infections from diverse pathogens, were 30.4%, 5.2%, and 0.9%, respectively, compared to 28.4%, 4.0%, and 0.0% in the sCRT group, revealing no significant differences. One patient in the I-sCRT group died from immune‐related pneumonitis during ICI consolidation treatment, and the cause of death was determined to be complicated by severe bacterial lung infection based on chest CT analysis. While no patient in the sCRT group died from RP. All other patients diagnosed with pneumonia fully recovered after treatment with oral or intravenous corticosteroids and additional supportive therapies. Generally, most of the treatment‐related toxicities in both groups were mild, predominantly classified as grades 1\u0026ndash;2. ICI treatment only led to a marginal significant statistical increase in abnormal thyroid function (hypothyroidism and hyperthyroidism) and hyperlipidemia, common adverse events of ICI treatment that are relatively manageable in clinical settings. Other toxicities showed no significant differences between the two groups. Among patients who received ICI treatment, fatigue was the most common grade 1\u0026ndash;2 toxicities (45.2%), followed by leukopenia (43.5%) and radiation esophagitis (40.9%). The most frequent severe (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) adverse events were hematologic toxicities, including leukopenia (10.4%), decreased platelet count (8.7%) and anemia (4.3%), followed by pneumonitis (5.2%).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOur study demonstrates that the incidence of treatment-related adverse events in the I-sCRT group is within an acceptable range, which confirming that the combination of ICI treatment and chemotherapy does not significantly increase the risk of adverse events in patients. To our knowledge, this multicenter retrospective study we conducted represents the largest investigation to date of the efficacy and safety of ICI treatment combined with definitive sCRT in patients with unresectable LA-NSCLC. The outcomes of this innovative treatment approach are encouraging, as indicated by a median PFS of 16.7 months and a median OS of 38.2 months. After performing PSM, the median PFS and OS still show significant statistical differences. Importantly, while severe adverse events were predominantly hematological, the overall treatment was well tolerated, thereby underscoring its favorable safety profile.\u003c/p\u003e \u003cp\u003eUpdated analyses from the phase III PACIFIC trial demonstrated that 42.9% of patients randomized to durvalumab remained alive at 5 years, with 33.1% maintaining progression-free survival. While cCRT showed superior survival outcomes compared to sCRT in unresectable LA-NSCLC patients\u0026mdash;attributable to enhanced locoregional control \u0026mdash;this benefit came with increased yet manageable acute esophageal toxicity. Real-world evidence reveals substantial treatment intolerance to cCRT, particularly among older adults (\u0026ge;\u0026thinsp;65 years) and patients with ECOG performance status\u0026thinsp;\u0026ge;\u0026thinsp;2, leading to sCRT becoming the preferred regimen in these subgroups\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Supporting this trend, a real-world study found older LA-NSCLC patients were significantly more likely to receive radiotherapy alone (40.1%) or sCRT (33.3%) than cCRT (26.6%)\u003csup\u003e12,13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe GEMSTONE-301 trial has established sugemalimab as an effective consolidation therapy for unresectable LA-NSCLC patients without disease progression after sCRT or cCRT. Notably, in the sCRT subgroup, sugemalimab demonstrated significantly prolonged progression-free survival (PFS) (8.08 vs. 4.07 months; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001)\u003csup\u003e8\u003c/sup\u003e. Supporting these findings, the PACIFIC-6 study revealed that durvalumab post-sCRT exhibited a safety profile consistent with the pivotal PACIFIC trial, with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs occurring in 18.8% of patients. Importantly, only 1.7% experienced grade 5 AEs, predominantly pneumonitis (2 cases). While the single-arm design precludes definitive efficacy conclusions, the observed median PFS of 10.9 months and 12-month OS rate of 84.1% are clinically encouraging\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Emerging evidence from PACIFIC-R real-world data further validates this approach, showing 3-year overall survival rates approaching 60% in sCRT-treated patients receiving durvalumab consolidation. Additionally, retrospective multicenter studies demonstrate comparable survival benefits between cCRT and sCRT subgroups when combined with durvalumab maintenance (PFS : 11.0 vs. 5.4 months; HR\u0026thinsp;=\u0026thinsp;0.75)\u003csup\u003e10\u003c/sup\u003e. The ongoing PACIFIC-5 phase III trial is prospectively evaluating durvalumab in sCRT populations, with interim analyses already indicating clinically meaningful PFS improvements. Collectively, these data strongly support the integration of immune checkpoint inhibitors (ICIs) with sCRT as a standard-of-care for unresectable LA-NSCLC, particularly in patients intolerant to cCRT.\u003c/p\u003e \u003cp\u003eConcurrent chemoradioimmunotherapy accelerates objective tumor response (shrinkage) and prolongs response duration. Robust evidence supports ICIs integration with CRT, as exemplified by the PACIFIC trial which achieved a 12-month duration of response (DoR) rate of 72.8%\u0026mdash;surpassed in the KEYNOTE-799 trial (NCT03631784, cohort A: 79.7%; cohort B: 75.6%)\u003csup\u003e14\u003c/sup\u003e. The Phase II APOLO study (NCT04131521) implemented a neoadjuvant regimen: atezolizumab\u0026thinsp;+\u0026thinsp;chemotherapy \u0026rarr; CCRT \u0026rarr; atezolizumab consolidation. This approach yielded 12-month PFS rates of 68.4% (intention-to-treat, ITT) and 78.1% (per-protocol, PP), with corresponding OS rates of 86.8% and 90.6% \u003csup\u003e15\u003c/sup\u003e. Considering that the combination of immunotherapy and chemotherapy has a better objective response rate (ORR), which can facilitate better surgery or radiotherapy, some clinical experts have already begun to try using it in the clinical practice of locally advanced lung cancer.\u003c/p\u003e \u003cp\u003eSafety analyses reveal ICI-specific toxicity patterns. The NICOLAS trial (NCT03628521) documented Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 pneumonitis in 11.7% (9/77) of nivolumab-treated patients, including one fatal event (Grade 5). Notably, 4 cases were radiation-attributable TRT\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Similarly, the DETERRED trial (NCT03818776) reported Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 immune-related toxicities in 20% (6/30) with cCRT\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. KEYNOTE-799 observed 7.4% (16/216) Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 pneumonitis, including 2.3% (5/216) fatalities. Atezolizumab-based regimens showed 27.4% (17/62) Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 immune-related AEs and 48.4% (30/62) treatment-related AEs, mirroring PACIFIC trial safety data with durvalumab\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. These findings underscore the necessity for risk-adapted monitoring protocols when combining ICIs with CRT.\u003c/p\u003e \u003cp\u003eIn real-world clinical practice, various factors may prevent every patient with unresectable stage III NSCLC from receiving the standard treatment regimens\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. A substantial subset of patients with potentially resectable stage III SCLC remain ineligible to undergo surgery following assessment after neo-adjuvant chemotherapy combined with immunotherapy. As a result, they often transition to radical radiotherapy followed by consolidating ICI. Furthermore, a significant proportion of patients with unresectable locally advanced disease present with large radiotherapy target volumes. After completing the planned chemotherapy and immunotherapy, these lesions may shrink, thereby providing the opportunity for subsequent radiotherapy. For the younger patient population, the treatment-related toxicities associated with chemotherapy combined with immunotherapy are deemed tolerable when weighed against the benefits of the treatment's efficacy. In clinical practice, the availability of immunotherapeutic agents and radiotherapy equipment, including limited availability in primary hospitals, as well as economic considerations, such as the coverage of medications by health insurance, also should be comprehensively evaluated. These factors have resulted in a significant proportion of patients in the real world adopting a treatment regimen involving chemotherapy combined with immunotherapy, followed by sequential radiotherapy and subsequent immunotherapy consolidation.\u003c/p\u003e \u003cp\u003eBuilding upon the PACIFIC and GEMSTONE-301 trial paradigms, in addition to the combinations of various chemotherapy, radiotherapy, and immunotherapy strategies that we just mentioned, the treatment paradigm for unresectable LA-NSCLC is continually evolving. As LAURA trail reported, treatment with EGFR tyrosine kinase inhibitor (TKI) osimertinib resulted in significantly longer PFS than placebo in patients with unresectable stage III EGFR-mutated NSCLC, demonstrating a mPFS of 39.1 vs. 5.6 months (HR 0.16, 95% CI 0.10\u0026ndash;0.25; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001)\u003csup\u003e19\u003c/sup\u003e. Patients with ALK-positive LA-NSCLC significantly improved rwPFS when treated with consolidation ALK-TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK-TKI therapy and durvalumab demonstrate an improvement in OS compared to observation alone, ALK-TKI therapy appears to be the superior option, highlighting its critical role in enhancing patient survival\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In another prospective study (SPRINT), treatment with induction pembrolizumab, risk-adapted thoracic radiotherapy without chemotherapy, and additional pembrolizumab produced promising safety and efficacy outcomes for patients with LA-NSCLC exhibiting high PD-L1 expression (TPS 50%). Approximately half of the patients demonstrated a response to three cycles of induction pembrolizumab, resulting in a 1-year PFS rate of 76% and OS rates of 92% and 76% at 1 and 2 years, respectively\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. All these results are encouraging and may be incorporated into treatment guidelines for specific subgroups of LA-NSCLC patients in the future, including the elderly, those with high PD-L1 expression, and patients harboring genetic mutations.\u003c/p\u003e \u003cp\u003eThis study demonstrates two key strengths. First, by systematically documenting the actual implementation rate of sCRT in clinical practice (55.0% vs. 45.0% in the cCRT population), it addresses the rigid treatment sequencing constraints typically encountered in traditional RCTs. Our real-world data collection preserves the clinical diversity in treatment decision-making, which is influenced by factors such as patient performance status and tumor response, thus providing direct evidence for evaluating the effectiveness of sequential therapy under real-world conditions. Second, our study encompasses three centers nationwide with a total of 1,604 cases, significantly surpassing previous multicenter investigations (e.g., 564 cases in the GEMSTONE-301 study\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e). Standardized data collection protocols, complemented by dual-entry verification, ensured comprehensive documentation of inter-institutional therapeutic variations (e.g., radiation fraction schemes and chemotherapy intervals), thereby enriching the interpretation of clinical contexts.\u003c/p\u003e \u003cp\u003eThis study acknowledges several limitations. First, as a retrospective investigation, its retrospective nature design may introduce confounding factors that can affect the evaluation of treatment efficacy. Second, there are issues of standardization in therapeutic protocols; the use of various ICIs\u0026mdash;each with different half-lives and immune-related adverse event profiles\u0026mdash;coupled with potential technical variations in linear accelerators and radiotherapy planning systems across institutions, which result in deviations from uniform dosing. Third, population specificity must be considered, as significant differences exist between Asian and Caucasian populations regarding immune checkpoint gene polymorphisms and tumor mutational burden thresholds, highlighting the need for further validation in non-Asian cohorts. Fourth, the systematic application of advanced evaluation modalities, such as PET-CT, was lacking, which may increase the risk of misdiagnosis related to pseudo-progression specific to immunotherapy (observed in 4%-10% of cases). The applicability of RECIST criteria in combined therapy settings is also limited, particularly since post-radiotherapy localized inflammatory responses may interfere with imaging assessments. Lastly, at baseline, the tumor PD-L1 expression was not available in more than one-third of the patients (n\u0026thinsp;=\u0026thinsp;36, 31.3%, and 90, 44.8%, respectively in I-sCRT and sCRT group). Future global multicenter prospective studies should incorporate standardized radiotherapy parameters, stratified analyses of ICI agents, and comparative cohorts across different ethnicities, thereby enhancing the reliability and generalizability of the evidence.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003e The analysis of this multicenter retrospective study showed a significant and clinically meaningful improvement in PFS and OS with the combination of ICI treatment before and after sCRT, which presents an effective and manageable treatment approach for patients with locally advanced, unresectable, stage III NSCLC without disease progression after chemoradiotherapy. We anticipate the results of future prospective studies to further validate this treatment approach.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest statement\u003c/h2\u003e \u003cp\u003eThe authors indicated no potential conflicts of interest.\u003c/p\u003e \u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis study was partially supported by CSCO - HANSOH Cancer Research Fund - Key Project (Subject No: Y-HS202102-0199), Shanghai Hospital Development Center Technical Specification Management and Promotion Project (Subject No: SHDC22024219). The study was approved by Ethics Committee of Shanghai Pulmonary Hospital (No. 19231ZL-1). The institutional review board at each center approved the study\u0026rsquo;s protocol. Written informed consent was taken from all the patients. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H. \u0026amp; Jemal, A. 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H. \u003cem\u003eet al.\u003c/em\u003e Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC. \u003cem\u003eJ Thorac Oncol\u003c/em\u003e 20, 109\u0026ndash;118 (2025). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jtho.2024.09.1379\u003c/span\u003e\u003cspan address=\"10.1016/j.jtho.2024.09.1379\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhri, N. \u003cem\u003eet al.\u003c/em\u003e Selective Personalized RadioImmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial (SPRINT). \u003cem\u003eJ Clin Oncol\u003c/em\u003e 42, 562\u0026ndash;570 (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.23.00627\u003c/span\u003e\u003cspan address=\"10.1200/JCO.23.00627\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"non-small cell lung cancer, immune checkpoint inhibitor, sequential chemoradiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-8849122/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8849122/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe aimed to assess the real-world effectiveness and toxicity of immune checkpoint inhibitor (ICI) treatment in unresectable stage III non-small cell lung cancer (NSCLC) patients who received ICIs before and after sequential chemoradiotherapy (sCRT) versus those who received sCRT alone.The study's primary endpoint was to evaluate the survival benefits of the treatment approach, with a focus on progression-free survival (PFS) and overall survival (OS), as well as treatment-related adverse events. From February 2018 to January 2023, 1,604 patients from three institutions were evaluated. Of these, 115 patients received ICI treatment both before and after sCRT (I-sCRT group), while 201 patients received only sCRT, serving as a control group (sCRT group). The inclusion of ICI treatment markedly improved PFS compared to those who received sCRT alone (HR 0.48, 95% CI 0.38\u0026ndash;0.61; log-rank p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median PFS was 16.7 months (95% CI 15.5\u0026ndash;21.7) in the I-sCRT group versus 9.9 months (95% CI 9.4\u0026ndash;11.9) in the sCRT group. OS was also significantly prolonged in I-sCRT group compared to sCRT group, with a median OS of 38.2 months (95% CI 33.2-NA) versus 27.1 months (95% CI 23.3\u0026ndash;35.4) (HR 0.64, 95% CI 0.47\u0026ndash;0.87; log-rank \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007). The overall safety profile of I-sCRT group was safe and controllable. The propensity score matching results before and after the analysis were consistent. Our analysis revealed a significant improvement in PFS and OS with the combination of ICI treatment administered both before and after sCRT, indicating an effective treatment strategy for patients with unresectable LA-NSCLC.\u003c/p\u003e","manuscriptTitle":"Sequential Chemoradiotherapy Combined with Immunotherapy Versus Sequential Chemoradiotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: A Multicenter Retrospective Cohort Study with Propensity Score Matching","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-19 16:12:05","doi":"10.21203/rs.3.rs-8849122/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6e774141-d0ce-4908-b4e7-2f3722600c76","owner":[],"postedDate":"March 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64608312,"name":"Health sciences/Oncology/Cancer/Lung cancer/Non-small-cell lung cancer"},{"id":64608313,"name":"Health sciences/Oncology/Cancer/Cancer therapy/Radiotherapy"}],"tags":[],"updatedAt":"2026-03-19T16:12:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-19 16:12:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8849122","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8849122","identity":"rs-8849122","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}